Age-Dependent Oxidative DNA Damage Does Not Correlate with Reduced Proliferation of Cardiomyocytes in Humans

PLoS One. 2017 Jan 18;12(1):e0170351. doi: 10.1371/journal.pone.0170351. eCollection 2017.

Abstract

Background: Postnatal human cardiomyocyte proliferation declines rapidly with age, which has been suggested to be correlated with increases in oxidative DNA damage in mice and plays an important role in regulating cardiomyocyte proliferation. However, the relationship between oxidative DNA damage and age in humans is unclear.

Methods: Sixty right ventricular outflow myocardial tissue specimens were obtained from ventricular septal defect infant patients during routine congenital cardiac surgery. These specimens were divided into three groups based on age: group A (age 0-6 months), group B (age, 7-12 months), and group C (>12 months). Each tissue specimen was subjected to DNA extraction, RNA extraction, and immunofluorescence.

Results: Immunofluorescence and qRT-PCR analysis revealed that DNA damage markers-mitochondrial DNA copy number, oxoguanine 8, and phosphorylated ataxia telangiectasia mutated-were highest in Group B. However immunofluorescence and qRT-PCR demonstrated that two cell proliferation markers, Ki67 and cyclin D2, were decreased with age. In addition, wheat germ agglutinin-staining indicated that the average size of cardiomyocytes increased with age.

Conclusions: Oxidative DNA damage of cardiomyocytes was not correlated positively with age in human beings. Oxidative DNA damage is unable to fully explain the reduced proliferation of human cardiomyocytes.

MeSH terms

  • Adolescent
  • Aging / physiology*
  • Ataxia Telangiectasia Mutated Proteins / genetics
  • Cell Proliferation / physiology*
  • Cells, Cultured
  • Child
  • Child, Preschool
  • Cyclin D2 / metabolism
  • DNA Copy Number Variations / genetics
  • DNA Damage / genetics*
  • DNA, Mitochondrial / genetics
  • Female
  • Guanine / analogs & derivatives
  • Guanine / metabolism
  • Heart Ventricles / metabolism*
  • Humans
  • Ki-67 Antigen / metabolism
  • Male
  • Mitochondria / metabolism
  • Myocytes, Cardiac / cytology
  • Myocytes, Cardiac / metabolism*
  • Oxidation-Reduction
  • Reverse Transcriptase Polymerase Chain Reaction

Substances

  • CCND2 protein, human
  • Cyclin D2
  • DNA, Mitochondrial
  • Ki-67 Antigen
  • 8-hydroxyguanine
  • Guanine
  • ATM protein, human
  • Ataxia Telangiectasia Mutated Proteins

Grants and funding

This work was supported by National Basic Research Program of China [grant number 2013CB945304] (http://www.most.gov.cn/); Natural Science Foundation of Shanghai (CN) (No.16ZR1421800)(http://www.stcsm.gov.cn) (http://kjc.shsmu.edu.cn/); Foundation of Shanghai Health and Family Planning Committee (CN) (No. 20164Y0106)(http://www.wsjsw.gov.cn); Foundation of Pudong science and technology development(PKJ2016-Y35)(http://www.techpudong.gov.cn/); Foundation of Shanghai Children’s Medical Center (YJY-SCMC2016-6)(www.scmc.com.cn).